Oral Biomarkers for HPV-related Head and Neck Cancer

描述（由申请人提供）：本申请是根据PA-11-159：预防相关癌症的生物标志物提交的。本研究的目的是鉴定人乳头瘤病毒相关头颈部鳞状细胞癌（HPV-HNSCC）的特异性生物标志物，以开发一种敏感和特异性的筛查工具来检测早期癌症，并鉴定可能发生HPV-HNSCC风险增加的HPV暴露个体亚群。我们计划通过评估HPV-HNSCC患者口腔冲洗样本（ORS）中HPV基因的甲基化来实现这一目标。病毒DNA整合到宿主基因组中是由于病毒调节基因的无意缺失而导致的癌症进展中发生的第一个分子步骤之一。在病毒整合后，HPV基因组也变得容易受到宿主表观遗传机制的修饰。因此，甲基化HPV基因的检测表明已经发生了病毒整合。由于病毒整合可导致细胞转化，因此ORS中整合或甲基化病毒基因的检测可成为诊断早期癌症和/或鉴定HPV暴露个体发生头颈癌风险增加的有用生物标志物。甲基化特异性PCR（MSP）是一种检测组织和体液中甲基化基因的成熟方法。通过MSP检测甲基化HPV基因在ORS可能是一种新的筛选工具，我们建议在这项研究中开发。当开发生物标志物时，通常通过鉴定和筛选那些具有最高癌症风险的受试者来提高成功率。被诊断患有HPV-HNSCC的患者的伴侣是处于持续口服HPV- 16暴露和感染风险的个体，这是HPV-HNSCC发展的已知风险因素。因此，我们计划在HPV-HNSCC患者和匹配伴侣的ORS中评估HPV基因甲基化。我们将比较患者、匹配伴侣和非癌症对照的ORS中甲基化或整合的HPV-16基因的检测频率，以确定甲基化的病毒基因，如L1，可以作为HPV-HNSCC的生物标志物，并确定HPV-HNSCC患者的伴侣是否代表可能处于HPV发展风险增加的HPV暴露个体的亚群。HNSCC是由于与匹配的对照组相比更高频率的持续性或综合性口腔HPV感染。已经收集了来自患者、伴侣和匹配对照的ORS，并准备用于本拟定研究。

DESCRIPTION (provided by applicant): This application is submitted in response to PA-11-159: Biomarkers of Infection-Associated Cancers. The objective of this study is to identify a biomarker specific for Human Papillomavirus-associated Head and Neck Squamous Cell Carcinoma (HPV-HNSCC) in order to develop a sensitive and specific screening tool to detect early stage cancers as well as to identify subpopulations of HPV-exposed individuals who may be at increased risk for developing HPV-HNSCC. We plan to achieve this goal by evaluating methylation of HPV genes in Oral Rinse Samples (ORS) of HPV-HNSCC patients. Integration of viral DNA into the host genome is one of the first molecular steps that occurs in the progression to cancer due to the inadvertent deletion of viral regulatory genes. After viral integration, the HPV genome also becomes susceptible to modification by the host epigenetic machinery. Therefore, the detection of methylated HPV genes indicates viral integration has occurred. Since viral integration can lead to cellular transformation, the detection of integrated, or methylated, viral genes in ORS can be a useful biomarker to diagnose early stage cancers and/or to identify HPV-exposed individuals at increased risk for developing head and neck cancer. Methylation-specific PCR (MSP) is an established method to detect methylated genes in tissue and body fluids. The detection of methylated HPV genes in the ORS via MSP may be a novel screening tool that we propose to develop in this study. When developing biomarkers, the success rate is often improved through the identification and screening of those subjects at highest risk for developing cancer. The partners of patients diagnosed with HPV-HNSCC are individuals at risk for persistent oral HPV- 16 exposure and infection, which is a known risk factor for the development of HPV-HNSCC. Therefore, we plan to evaluate for HPV gene methylation in the ORS of both HPV-HNSCC patients and matched partners. We will compare the frequency of detection of methylated, or integrated, HPV-16 genes in the ORS of patients, matched partners, and non-cancer controls to determine if methylated viral genes, such as L1, can serve as a biomarker for HPV-HNSCC and to determine if the partners of HPV-HNSCC patients represent a subpopulation of HPV-exposed individuals who may be at increased risk for developing HPV-HNSCC due to a higher frequency of persistent, or integrated, oral HPV infection as compared to a matched control group. The ORS from patients, partners, and matched controls already have been collected and are ready to be used for this proposed study.